Electrical wire properties of DNA linked to cancer

Electrons travel through DNA to signal repair proteins to find and fix damage. An electron travels from one protein to the next or vice versa, and then adds to the protein's iron-sulfur cluster. With the extra electron, the protein falls off the DNA, signaling that there is no DNA damage. But if there is damage to the DNA, the electron won't make it to a protein's iron-sulfur cluster, so that the protein stays bound to DNA—and inches toward the damage to fix it.

One of the biggest helpers in our bodies' ongoing efforts to prevent DNA mutations -- mutations that can lead to cancer -- is actually rather tiny. Electrons, as it turns out, can signal proteins that repair DNA to patch up DNA damage. More specifically, the movement of electrons through DNA, traveling between repair proteins bound to the double helix, helps our cells scan for mistakes that regularly arise in our DNA.

DNA charge transport is used to repair DNA in the following way: Various DNA repair proteins bind to the double helix at different locations. Electrons are then sent traveling down DNA from one protein to another, as if the double helix were acting like an electrical wire. If the DNA is intact, with no damage, the electron goes through and reaches the next repair protein, signaling it to drop off the DNA strand. If there is damage along the way, however, the electron won't reach the next DNA repair protein. The repair protein stays bound to the DNA and continues to inch toward the damage. It's like an electrician finding a break in the line.

"These DNA repair proteins can slide along the DNA, scanning for mutations," says Phillip Bartels, a postdoctoral scholar in chemistry and one of three lead authors of the new study. "DNA damage breaks the 'wire,' preventing the electron from reaching the next protein."

The iron-sulfur clusters in the DNA repair proteins are the source of the electrons. When the proteins gain an electron via this cluster, their affinity for DNA drops and they fall off the DNA. When the proteins lose an electron, their affinity for the DNA increases. The process of losing and gaining electrons is known as redox chemistry.

"This reversible redox chemistry acts like an on and off switch to control the binding of proteins to DNA," says graduate student Elizabeth (Liz) O'Brien, who led a related study showing that DNA charge transport is at work in DNA replication.

In the new study, the scientists performed a series of electrochemical experiments that showed that the C306W mutation in the repair protein MUTYH causes the iron-sulfur cluster to be degraded when exposed to oxygen. Once degraded, the MUTYH repair protein can't do its job.

In the future, this kind of research could lead to useful diagnostics for cancer patients or even personalized medicine. "This is only the tip of the iceberg," says Bartels. "There may be other mutations in cancer patients besides C306W that similarly disrupt this charge transport process.